Sulfonamides

ABSTRACT

The present invention relates to sulfonamides, pharmaceutical compositions containing them, and their use as antagonists of urotensin II.

FIELD OF THE INVENTION

[0001] The present invention relates to sulfonamides, pharmaceuticalcompositions containing them and their use as urotensin II antagonists

BACKGROUND OF THE INVENTION

[0002] The integrated control of cardiovascular homeostasis is achievedthrough a combination of both direct neuronal control and systemicneurohormonal activation. Although the resultant release of bothcontractile and relaxant factors is normally under stringent regulation,an aberration in this status quo can result in cardiohemodynamicdysfunction with pathological consequences.

[0003] The principal mammalian vasoactive factors that comprise thisneurohumoral axis, namely angiotensin-II, endothelin-1, norepinephrine,all function via an interaction with specific G-protein coupledreceptors (GPCR). Urotensin-II, represents a novel member of thisneurohumoral axis.

[0004] In the fish, this peptide has significant hemodynamic andendocrine actions in diverse end-organ systems and tissues:

[0005] smooth muscle contraction

[0006] both vascular and non-vascular in origin including smooth musclepreparations from the gastrointestinal tract and genitourinary tract.Both pressor and depressor activity has been described upon systemicadministration of exogenous peptide

[0007] osmoregulation:

[0008] effects which include the modulation of transepithelial ion (Na⁺,Cl⁻) transport. Although a diuretic effect has been described, such aneffect is postulated to be secondary to direct renovascular effects(elevated GFR)

[0009] metabolism:

[0010] urotensin-II influences prolactin secretion and exhibits alipolytic effect in fish (activating triacylglycerol lipase resulting inthe mobilization of non-esterified free fatty acids)

[0011] (Pearson, et. al. Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77,5021;Conlon, et. al. J. Exp. Zool. 1996, 275, 226.)

[0012] In studies with human Urotensin-II it was found that it:

[0013] was an extremely potent and efficacious vasoconstrictor

[0014] exhibited sustained contractile activity that was extremelyresistant to wash out

[0015] had detrimental effects on cardiac performance (myocardialcontractility)

[0016] Human Urotensin-II was assessed for contractile activity in therat-isolated aorta and was shown to be the most potent contractileagonist identified to date. Based on the in vitro pharmacology and invivo hemodynamic profile of human Urotensin-II it plays a pathologicalrole in cardiovascular diseases characterized by excessive or abnormalvasoconstriction and myocardial dysfunction. (Ames et. al. Nature 1999,401, 282; Douglas & Ohlstein (2001). Trends Cardiovasc. Med., 10: inpress).

[0017] Compounds that antagonize the Urotensin-II receptor may be usefulin the treatment of congestive heart failure, stroke, ischemic heartdisease (angina, myocardial ischemia), cardiac arrhythmia, hypertension(essential and pulmonary), COPD, fibrosis (e. g. pulmonary fibrosis),restenosis, atherosclerosis, dyslipidemia, asthma, (Hay DWP, Luttmann MA, Douglas S A: 2000, Br J Pharmacol: 131; 10-12) neurogenicinflammation and metabolic vasculopathies all of which are characterizedby abnormal vasoconstriction and/or myocardial dysfunction. Urotensinantagonists may provide end organ protection in hypersensitive cohortsin addition to lowering blood pressure.

[0018] Since U-II and GPR14 are both expressed within the mammalian CNS(Ames et. al. Nature 1999, 401, 282), they also may be useful in thetreatment of addiction, schizophrenia, cognitive disorders/Alzheimersdisease, (Gartlon J. Psychopharmacology (Berl) 2001 June;155(4):426-33), impulsivity, anxiety, stress, depression, pain,migraine, neuromuscular function, parkinsons, movement disorders,sleep-wake cycle, and incentive motivation (Clark et al. Brain Research923 (2001) 120-127.

[0019] Functional U-II receptors are expressed in rhabdomyosarcomas celllines and therefore may have oncological indications. Urotensin may alsobe implicated in various metabolic diseases such as diabetes (Ames et.al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1:383-385, 1999) and in various gastrointestinal disorders, bone,cartilage, and joint disorders (e. g. arthritis and osteoporosis); andgenito-urinary disorders. Therefore, these compounds may be useful forthe prevention (treatment) of gastric reflux, gastric motility andulcers, arthritis, osteoporosis and urinary incontinence.

SUMMARY OF THE INVENTION

[0020] In one aspect this invention provides for sulfonamides andpharmaceutical compositions containing them.

[0021] In a second aspect, this invention provides for the use ofsulfonamides as antagonists of urotensin II, and as inhibitors ofurotensin II.

[0022] In another aspect, this invention provides for the use ofsulfonamides for treating conditions associated with urotensin IIimbalance.

[0023] In yet another aspect, this invention provides for the use ofsulfonamides for the treatment of congestive heart failure, stroke,ischemic heart disease (angina, myocardial ischemia), cardiacarrhythmia, hypertension (essential and pulmonary), renal disease (acuteand chronic renal failure/end stage renal disease) along with peripheralvascular disease (male erectile dysfunction, diabetic retinopathy,intermittent claudication/ischemic limb disease) andischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenicinflammation, migraine, metabolic vasculopathies, bone/cartilage/jointdiseases, arthritis and other inflammatory diseases, fibrosis (e. g.pulmonary fibrosis), sepsis, atherosclerosis, dyslipidemia, addiction,schizophrenia, cognitive disorders/Alzheimers disease, impulsivity,anxiety, stress, depression, parkinsons, movement disorders, sleep-wakecycle, incentive motivation, pain, neuromuscular function, diabetes,gastric reflux, gastric motility disorders, ulcers and genitourinarydiseases.

[0024] The urotensin antagonist may be administered alone or inconjunction with one or more other therapeutic agents, said agents beingselected from the group consisting of endothelin receptor antagonists,angiotensin converting enzyme (ACE) inhibitors, A-II receptorantagonists, vasopeptidase inhibitors, diuretics, digoxin, and dualnon-selective β-adrenoceptor and α₁-adrenoceptor antagonists.

[0025] Other aspects and advantages of the present invention aredescribed further in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides for compounds of Formula (I):

[0027] wherein:

[0028] Ar is phenyl, thienyl, furanyl, pyridinyl, oxazoyl, pyrroyl,triazinyl, imidazoyl, pyrimidinyl, pyrazinyl, oxadiazoyl, pyrazoyl,triazoyl, thiazoyl, thiadiazoyl, quinolinyl, quinazolinyl,naphthyridinyl, azaspirononoyl, benzodioxanyl, benzodioxoyl, orbenzodioxepinyl, substituted or unsubstituted by one, two, three or fourof the following: halogen, CN, S(C₁₋₆ alkyl), CF₃, OCF₃, SCF₃, C₁₋₆alkyl, C₁₋₆ alkoxy, CO₂(C₁₋₆ alkyl), NR₉R₁₀, CONR₇R₈, or NO₂;

[0029] A is phenyl, thienyl, furanyl, pyridinyl, oxazoyl, pyrroyl,triazinyl, imidazoyl, pyrimidinyl, pyrazinyl, N-phenylpyrroyl,oxadiazoyl, pyrazoyl, triazoyl, thiazoyl, thiadiazoyl, naphthyl, indoyl,quinolinyl, quinazolinyl, naphthyridinyl, benzothiophenyl, benzofuranyl,benzothiazoyl, benzoxazoyl, benzodioxanyl, benzodioxoyl,benzodioxepinyl, benzothiadiazoyl, benzoxadiazoyl, or benzimidazoyl, allof which may be substituted or unsubstituted by one, two, three or fourhalogens, C₁₋₆ alkyl, C₁₋₆ alkoxy, CO₂(C₁₋₆ alkyl), CN, or CF₃ groups;

[0030] Y is O, NH, —S(O_(n))—, CH₂, or a bond;

[0031] R₂ is hydrogen, halogen, CF₃, CN, or C₁₋₄ alkyl;

[0032] R₃, R₄, R₇, and R₈ are independently hydrogen, C₁₋₆ alkyl, orbenzyl;

[0033] R₅, R₆, R₉, and R₁₀ are independently hydrogen or C₁₋₆ alkyl;

[0034] X is O, S, or CH₂;

[0035] n is 0, 1, or 2;

[0036] or a pharmaceutically acceptable salt thereof.

[0037] When used herein, the term “alkyl” includes all straight chainand branched isomers. Representative examples thereof include methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl,n-pentyl and n-hexyl.

[0038] When used herein, the terms ‘halogen’ and ‘halo’ includefluorine, chlorine, bromine and iodine and fluoro, chloro, bromo andiodo, respectively.

[0039] The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeform. All of these compounds and their diastereoisomers are contemplatedto be within the scope of the present invention. Preferably Ar is phenylwhich may be substituted or unsubstituted by halogen, CN, SMe, YCF₃,C₁₋₄ alkyl or NO₂.

[0040] Preferably Ar is phenyl, benzodioxoyl, or pyrimidinyl which maybe substituted or unsubstituted by halogen, CN, S(C₁₋₆ alkyl), CF₃, C₁₋₆alkyl, C₁₋₆ alkoxy, or NO₂.

[0041] Preferably A is phenyl or thienyl which may be substituted orunsubstituted by halogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

[0042] Preferably Y is O, —S(O₂)—, or a bond.

[0043] Preferably R₂ is halogen or CF₃.

[0044] Preferably R₃ is C₁₋₆ alkyl; more preferably R₃ is methyl orethyl.

[0045] Preferably R₄ is C₁₋₆ alkyl; more preferably R₄ is methyl orethyl.

[0046] Preferably R₅ and R₆ are hydrogen.

[0047] Preferably X is O or CH₂.

[0048] Preferred Compounds are:

[0049]4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;

[0050] 5-Benzenesulfonyl-thiophene-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;

[0051]3,5-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-chloro-4-nitrophenoxy)-benzenesulfonamide;

[0052] 5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;

[0053]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3-(4-chloro-phenoxy)-benzenesulfonamide;

[0054]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-phenoxy-benzenesulfonamide;

[0055]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(4-methoxy-phenoxy)-benzenesulfonamide;

[0056]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,4-dichloro-phenoxy)-benzenesulfonamide;

[0057]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-chloro-phenoxy)-benzenesulfonamide;

[0058]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-methyl-phenoxy)-benzenesulfonamide;

[0059]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-trifluoromethyl-phenoxy)-benzenesulfonamide;

[0060]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,5-dichloro-phenoxy)-benzenesulfonamide;

[0061]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,4-dichloro-phenoxy)-benzenesulfonamide;

[0062]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3-(3,5-dichloro-phenoxy)-benzenesulfonamide;

[0063]2-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;

[0064]2-Methyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;

[0065]2,6Dimethyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;

[0066]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(4-chloro-phenoxy)-benzenesulfonamide;

[0067]3,5-Dichloro-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-4-(2-chloro-4-nitro-phenoxy)-benzenesulfonamide;

[0068]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-phenoxy)-benzenesulfonamide;

[0069]N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3-chloro-phenoxy)-benzenesulfonamide;

[0070] Biphenyl4-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;

[0071] 4′-Chloro-biphenyl-4-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;3′,4′-Dichloro-biphenyl-4-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;

[0072]4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-benzenesulfonamidehydrochloride;

[0073]2-methyl-5-methoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;

[0074] 4,5-Dimethoxy-biphenyl-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;

[0075]2-Benzo[1,3]dioxol-5-yl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide;

[0076]4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-(3-diethylamino-propyl)-phenyl]-benzenesulfonamide;

[0077]N-[4-Chloro-3-(2-dimethylamino-propoxy)-phenyl]-4-(3-chloro-2-methyl-phenoxy)-benzenesulfonamide;

[0078]4-(3-Chloro-2-cyano-phenoxy)-N-[4chloro-3-((S)-3-dimethylamino-but-2-oxy)-phenyl]-benzenesulfonamide;

[0079]4-(3-Chloro-2cyano-phenoxy)-N-[4-chloro-3-((R)-3-dimethylamino-but-2-oxy)-phenyl]-benzenesulfonamide;and

[0080]4-(3-Chloro-2-cyano-phenoxy)-N-[3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenyl]-benzenesulfonamide.

[0081] More preferred compounds are:

[0082]4-(3-Chloro-2cyano-phenoxy)-N-[4chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;

[0083]4-(2-Chloro-4-nitro-phenoxy)-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3,5-dichloro-benzenesulfonamide;

[0084]3-(3,5-Dichloro-phenoxy)-N-[4chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;

[0085]4-(2-Cyano-3-chloro-phenoxy)-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-chloro-benzenesulfonamide;

[0086]4-(2-Cyano-3-chloro-phenoxy)-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-methyl-benzenesulfonamide;

[0087]4-(2-Cyano-3-chloro-phenoxy)-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2,6-dimethyl-benzenesulfonamide;

[0088]3-(3-Chloro-2-cyanophenoxy)-N-[3-(2-dimethylaminoethoxy)-4-trifluoromethylphenyl]-benzenesulfonamide;and

[0089]4-(3-Chloro-2-cyano-phenoxy)-N-[3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenyl]-benzenesulfonamide.

[0090] Compounds of Formula (I) wherein X is oxygen, and R₅ and R₆ arehydrogen are prepared as outlined in Scheme 1.

[0091] Conditions: a) 48% hydrogen bromide, acetic acid; b) hydrogen (50psi), platinum on carbon, ethyl acetate; c) di-tert-butyldicarbonate,tetrahydrofuran, reflux; d) ClCH₂CH₂NR₃R₄-hydrochloride, potassiumcarbonate, water/1,2-dimethoxyethane, reflux; e) 6 N hydrogen chloride;f) Ar—Y-A-SO₂Cl, chloroform, ambient temperature. Ar, A, Y, R₂, R₃, andR₄ are as defined in Formula (I).

[0092] For example, acid-mediated demethylation of anisoles 1 gavephenols 2. Hydrogenation of the nitro group provided anilines 3, whichwere subsequently protected as their tert-butoxycarbonyl carbamates 4.Alkylation of 4 with various dialkylaminoethyl chlorides, followed byremoval of the nitrogen protecting group afforded anilines 5. Subsequentsulfonylation of the anilines furnished the target compounds 6.

[0093] Preparation of Ar—Y-A-SO₂Cl that were not available commerciallyis set forth in scheme 2:

[0094] Conditions: a) Sodium hydride, dimethylsulfoxide; then2,6-dichlorobenzonitrile, 100° C. ; b) chlorosulfonic acid,dichloromethane, 0° C. to ambient temperature. R is defined as halo,methyl, or methoxy.

[0095] Various phenols 1 were alkylated with 2,6-dichlorobenzonitrile toprovide ethers 2. Treatment of 2 with chlorosulfonic acid furnished thedesired sulfonyl chlorides 3.

[0096] Compounds wherein Y is a bond are prepared as set forth in scheme3.

[0097] Conditions: a) chlorosulfonic acid, dichloromethane, 0° C. toambient temperature; b) dichloroethane, ambient temperature; c)ArB(OH)₂, Pd(PPh₃)₄, cesium carbonate, 90° C. Ar is as defined I Formula(I).

[0098] Preparation of biphenyl analogs began by chlorosulfonation of4-bromoveratrole (1) to give sulfonyl chloride 2. Coupling of 2 withaniline 3 at ambient temperature furnished sulfonamide 4.Palladium(0)-mediated Suzuki couplings using a range of arylboronicacids provided the desired biphenyl compounds 5.

[0099] Compounds wherein X is CH₂ are prepared as set forth in scheme 4:

[0100] Conditions: a) diethylamine,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,1-hydroxybenzotriazole hydrate, chloroform, ambient temperature; b)hydrogen (50 psi), 5% platinum on carbon, ethyl acetate; c) 1 Mborane-tetrahydrofuran in tetrahydrofuran, relux; d) Ar—Y-A-SO₂Cl,chloroform, ambient temperature. Ar, A, Y, R₂, R₃, and R₄ are as definedin Formula (I).

[0101] Preparation of analogs in which the dialylamino side chain islinked by an all carbon linker were derived from2-chloro-5-nitrocinnamic acid (1). Coupling of 1 to variousdialkylamines provided amides 2. Reductions of both the nitro groups andthe side chain double bonds were accomplished with hydrogen (50 psi) andplatinum on carbon to give anilines 3. Borane reductions of 3, followedby sulfonylations of the anilines furnished the desired sulfonamides 5.

[0102] Compounds wherein at least one of R₅ and R₆ is other thanhydrogen are prepared as set forth in scheme 5:

[0103] Conditions: a) R₅CH(Cl)COR₆, potassium carbonate, potassiumiodide, acetone, reflux; b) R₃R₄NH-hydrochloride, methanol, sieves,reflux; then sodium cyanoborohydride; then 6 N hydrogen chloride,ambient temperature; c) Ar—Y-A-SO₂Cl, chloroform, ambient temperature.Ar, A, Y, R₂, R₃, and R₄ are as defined in Formula (I).

[0104] Alkylation of phenol 1 with various alpha-chloro-ketones provided2. Reductive amination of the ketones 2 with various dialkylamines,followed by removal of the nitrogen protecting group gave anilines 3.Sulfonylations of 3 furnished the desired sulfonamides 4.

[0105] Compounds wherein R₂ is CF₃ may be prepared as follows:

[0106] Conditions: a) benzophenone imine, 150° C. ; b) NaH,HOCH₂CH₂NR₃R₄, dimethylforamide, ambient temperature; then 2, 100° C. ;c) 1 N hydrochloric acid, reflux; d) R₁—SO₂Cl, chloroform, ambienttemperature. Ar, Y, A, R₃, and R₄ are as defined in Formula (I).

[0107] For example, treatment of 3-fluoro4-trifluoromethylaniline (1)with benzophenone imine afford imine 2. Displacement of the fluoride wasaccomplished with various sodium alkoxides to provide ethers 3.Conversion of the imine back to the aniline, followed by sulfonylationwith various sulfonyl chlorides furnished the desired sulfonamides 5.

[0108] In order to use a compound of the Formula (I) or apharmaceutically acceptable salt thereof for the treatment of humans andother mammals it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

[0109] Compounds of Formula (I) and their pharmaceutically acceptablesalts may be administered in a standard manner for the treatment of theindicated diseases, for example orally, parenterally, sub-lingually,transdermally, rectally, via inhalation or via buccal administration.

[0110] Compounds of Formula (I) and their pharmaceutically acceptablesalts which are active when given orally can be formulated as syrups,tablets, capsules and lozenges. A syrup formulation will generallyconsist of a suspension or solution of the compound or salt in a liquidcarrier for example, ethanol, peanut oil, olive oil, glycerine or waterwith a flavoring or coloring agent. Where the composition is in the formof a tablet, any pharmaceutical carrier routinely used for preparingsolid formulations may be used. Examples of such carriers includemagnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia,stearic acid, starch, lactose and sucrose. Where the composition is inthe form of a capsule, any routine encapsulation is suitable, forexample using the aforementioned carriers in a hard gelatin capsuleshell. Where the composition is in the form of a soft gelatin shellcapsule any pharmaceutical carrier routinely used for preparingdispersions or suspensions may be considered, for example aqueous gums,celluloses, silicates or oils and are incorporated in a soft gelatincapsule shell.

[0111] Typical parenteral compositions consist of a solution orsuspension of the compound or salt in a sterile aqueous or non-aqueouscarrier optionally containing a parenterally acceptable oil, for examplepolyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, orsesame oil.

[0112] Typical compositions for inhalation are in the form of asolution, suspension or emulsion that may be administered as a drypowder or in the form of an aerosol using a conventional propellant suchas dichlorodifluoromethane or trichlorofluoromethane.

[0113] A typical suppository formulation comprises a compound of Formula(1) or a pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats or their synthetic analogues.

[0114] Typical transdermal formulations comprise a conventional aqueousor non-aqueous vehicle, for example a cream, ointment, lotion or pasteor are in the form of a medicated plaster, patch or membrane.

[0115] Preferably the composition is in unit dosage form, for example atablet, capsule or metered aerosol dose, so that the patient mayadminister to themselves a single dose.

[0116] Each dosage unit for oral administration contains suitably from0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and eachdosage unit for parenteral administration contains suitably from 0.1 mgto 100 mg, of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof calculated as the free acid. Each dosage unit forintranasal administration contains suitably 1-400 mg and preferably 10to 200 mg per person. A topical formulation contains suitably 0.01 to1.0% of a compound of Formula (I).

[0117] The daily dosage regimen for oral administration is suitablyabout 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or apharmaceutically acceptable salt thereof calculated as the free acid.The daily dosage regimen for parenteral administration is suitably about0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or apharmaceutically acceptable salt thereof calculated as the free acid.The daily dosage regimen for intranasal administration and oralinhalation is suitably about 10 to about 500 mg/person. The activeingredient may be administered from 1 to 6 times a day, sufficient toexhibit the desired activity.

[0118] These sulphonamide analogs may be used for the treatment ofcongestive heart failure, stroke, ischemic heart disease (angina,myocardial ischemia), cardiac arrhythmia, hypertension (essential andpulmonary), renal disease (acute and chronic renal failure/end stagerenal disease) along with peripheral vascular disease (male erectiledysfunction, diabetic retinopathy, intermittent claudication/ischemiclimb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma,neurogenic inflammation, migraine, metabolic vasculopathies,bone/cartilage/joint diseases, arthritis and other inflammatorydiseases, fibrosis (e. g. pulmonary fibrosis), sepsis, atherosclerosis,dyslipidemia, addiction, schizophrenia, cognitive disorders/Alzheimersdisease, impulsivity, anxiety, stress, depression, pain, neuromuscularfunction, diabetes, gastric reflux, gastric motility disorders, ulcersand genitourinary diseases.

[0119] The urotensin antagonist may be administered alone or inconjunction with one or more other therapeutic agents, said agents beingselected from the group consisting of endothelin receptor antagonists,angiotensin converting enzyme (ACE) inhibitors, A-II receptorantagonists, vasopeptidase inhibitors, diuretics, digoxin, and dualnon-selective β-adrenoceptor and α₁-adrenoceptor antagonists.

[0120] No unacceptable toxicological effects are expected when compoundsof the invention are administered in accordance with the presentinvention.

[0121] The biological activity of the compounds of Formula (1) aredemonstrated by the following tests:

[0122] Radioligand Binding:

[0123] HEK-293 cell membranes containing stable cloned human and ratGPR-14 (20 ug/assay) were incubated with 200 pM [125I] h-U-II (200Ci/mmol⁻¹ in the presence of increasing concentrations of test compoundsin DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 mMTris-HCl, 5 mM MgCl2). Incubation was done for 30 minutes at roomtemperature followed by filtration GF/B filters with Brandel cellharvester. ¹²⁵I labeled U-II binding was quantitated by gamma counting.Nonspecific binding was defined by ¹²⁵I U-II binding in the presence of100 nM of unlabeled human U-II. Analysis of the data was performed bynonlinear least square fitting.

[0124] Ca²⁺-Mobilization:

[0125] A microtitre plate based Ca²⁺-mobilization FLIPR assay (MolecularDevices, Sunnyvale, Calif.) was used for the functional identificationof the ligand activating HEK-293 cells expressing (stable) recombinantGPR-14. The day following transfection, cells were plated in apoly-D-lysine coated 96 well black/clear plates. After 18-24 hours themedia was aspirated and Fluo 3AM-loaded cells were exposed to variousconcentrations (10 nM to 30 uM) of test compounds followed by h-U-II.After initiation of the assay, fluorescence was read every second forone minute and then every 3 seconds for the following one minute. Theinhibitory concentration at 50% (IC50)was calculated for various testcompounds.

[0126] Inositol Phosphates Assays:

[0127] HEK-293-GPR14 cells in T150 flask were prelabeled overnight with1 uCi myo-[³H] inositol per ml of inositol free Dulbecco's modifiedEagel's medium. After labeling, the cells were washed twice withDulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBScontaining 10 mM LiCl for 10 min at 37° C. The experiment was initiatedby the addition of increasing concentrations of h-U-II (1 pM to 1 μM) inthe absence and presence of three different concentrations (0.3, 1 and10 uM) of test compounds and the incubation continued for an additional5 min at 37° C. after which the reaction was terminated by the additionof 10% (final concentration) trichloroacetic acid and centrifugation.The supernatants were neutralized with 100 ul of 1M Trizma base and theinositol phosphates were separated on AG 1-X8 columns (0.8 ml packed,100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8ml of 200 mM ammonium formate. Combined inositol di and tris phosphatewas eluted with 4 ml of 1M ammonium formate/0.1 M formic acid. Elutedfractions were counted in beta scintillation counter. Based on shiftfrom the control curve K_(B) was calculated.

[0128] Activity for the compounds of this invention range from(radioligand binding assay): Ki=50 nM-10000 nM (example 19 Ki=520 nM).

[0129] The following Examples are illustrative but not limitingembodiments of the present invention.

EXAMPLE 14-(3-Chloro-2-cyano-phenoxy)N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide.

[0130]

[0131] a). 2-Chloro-5-nitrophenol

[0132] 2-Chloro-5-nitroanisole (310 g, 1.7 mol) was taken up in amixture of 48% HBr (1.5 L) and AcOH (1.2 L) and heated at reflux for 3days. The dark solution was allowed to cool to room temperature, pouredinto ice water (10 L), and let stand for 3 h. The resultant dull yellowsolid was filtered, washed with water, and dried in vacuo (230 g, 79%):mp 115-117° C.

[0133] b). 2-Chloro-5-aminophenol

[0134] A solution of 2-chloro-5-nitrophenol (25 g, 0.14 mol) in ethylacetate (150 mL) was treated with 5% Pt/C (250 mg) and the mixtureshaken under a hydrogen atmosphere (30 psi) for 4 h. The mixture wasfiltered through Celite® and the residue washed well with hot ethylacetate. The filtrate was treated with activated charcoal andre-filtered as above. Evaporation of the ethyl acetate gave a solid(19.8 g, 98%).

[0135] c). 4-Chloro-3-hydroxyphenylcarbamic acid tert-butyl ester

[0136] To a solution of 2-chloro-5-aminophenol (20 g, 0.14 mol) in THF(150 mL) was added a solution of di-tert-butyl dicarbonate (33 g, 0.15mol) in THF (150 mL). The reaction was heated at reflux for 6 h, atwhich time it was allowed to cool to room temperature. The solvent wasremoved in vacuo and the residue diluted with ether (500 mL) and washedwith 1 M citric acid (2×300 mL). The aqueous washings were extractedwith ether (300 mL) and the combined organics washed with brine (300mL), dried (MgSO₄), and concentrated. The resultant brown solid wastriturated with hexanes and dried in vacuo to give 33 g (97%) of thetitle compound: mp 103-106° C.

[0137] d). 3-[2-(N,N-Dimethylamino)ethoxy]-4-chloroaniline

[0138] To a solution of 4-chloro-3-hydroxyphenylcarbamic acid tert-butylester (140 mg, 0.57 mmol) in 4:1 DME/water (5 mL) was addeddimethylaminoethyl chloride hydrochloride (90 mg, 0.63 mmol) and K₂CO₃(320 mg, 2.3 mmol). The reaction mixture was heated at reflux for 16 h,at which time it was allowed to cool to room temperature. The DME wasremoved in vacuo and the residue treated with 6 N HCl (2 mL). Theresultant mixture was stirred at room temperature for 2 h, at which timeit was diluted with water (5 mL) and washed with EtOAc (5 mL). Theaqueous layer was basified with solid K₂CO₃ and extracted with EtOAc(2×10 mL). The EtOAc layers were washed with brine (10 mL), dried(MgSO₄), and concentrated to give 60 mg (50%) of the title compound.

[0139] e)4-(3-Chloro-2-cyano-phenoxy)N-[4chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide

[0140] 3-[2-(N,N-Dimethylamino)ethoxy]-4-chloro-aniline (0.05 g, 0.23mmol) was dissolved in CHCl₃ (0.5 mL). A solution of4-(2-cyano-3-chloro-phenoxy)benzenesulfonyl chloride (0.076 g, 0.23mmol) in CHCl₃ (0.5 mL) was added and the solution was allowed to shakefor 5 days. The solution was evaporated and the residue purified bypreparative reverse phase HPLC to give the title compound (0.05 g, 43%).

[0141] MS (ES+) m/e 506 [M+H]⁺

[0142] Examples 2-18 were prepared as in Example I substituting theappropriate starting materials. MS (ES+) m/e Example Compound [M+H]⁺

5-Benzenesulfonyl-thiophene-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)- phenyl]-amide 501 2

3,5-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-chloro-4-nitro-phenoxy)-benzenesulfonamide 594 3

5-(2-Methylsulfanyl-pyrimidin-4-yl)- thiophene-2-sulfonic acid[4-chloro-3-(2- dimethylamino-ethoxy)-phenyl]-amide 485 4

N-[4-chloro-3-(2-dimethylamino-ethoxy)- phenyl]-3-(4-chloro-phenoxy)-benzenesulfonamide 481 5

N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-phenoxy-benzenesulfonamide 447 6

N-[4-chloro-3-(2-dimethylamino-ethoxy)- phenyl]-4-(4-methoxy-phenoxy)-benzenesulfonamide 477 7

N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,4-dichloro-phenoxy)- benzenesulfonamide 515 8

N-[4-chloro-3-(2-dimethylamino-ethoxy)- phenyl]-4-(2-chloro-phenoxy)-benzenesulfonamide 481 9

N-[4-chloro-3-(2-dimethylamino-ethoxy)- phenyl]-4-(2-methyl-phenoxy)-benzenesulfonamide 461 10

N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-trifluoromethyl-phenoxy)- benzenesulfonamide 515 11

N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,5-dichloro-phenoxy)- benzenesulfonamide 515 12

N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,4-dichloro-phenoxy)- benzenesulfonamide 515 13

N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3-(3,5-dichloro-phenoxy)- benzenesulfonamide 515 14

2-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro- phenoxy)-benzenesulfonamide 540 15

2-Methyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro- phenoxy)-benzenesulfonamide 520 16

2,6-Dimethyl-N-[4-chloro-3-(2- dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide 534 17

N-[4-Chloro-3-(2-dimethylamino-ethoxy)- phenyl]-4-(4-chloro-phenoxy)-benzenesulfonamide 481 18

3,5-Dichloro-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-4-(2-chloro-4-nitro- phenoxy)-benzenesulfonamide 622 19

N-[4-Chloro-3-(2-dimethylamino-ethoxy)- phenyl]-4-(2-cyano-phenoxy)-benzenesulfonamide 472 20

N-[4-Chloro-3-(2-dimethylamino-ethoxy)- phenyl]-4-(3-chloro-phenoxy)-benzenesulfonamide 481 21

Biphenyl-4-sulfonaic acid [4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide 431 22

4′-Chloro-biphenyl-4-sulfonic acid [4-3-(2-dimethylamino-ethoxy)-phenyl]-amide 465 23

3′,4′-Dichloro-biphenyl-4-sulfonic acid [4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]- amide 499 24

4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]- benzenesulfonamide hydrochloride 53425

2-Methyl-5-methoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide 550 26

EXAMPLE 16a 4-(3-Chloro-2-cyano-phenoxy)-2-methyl-benzenesulfonylchloride

[0143]

[0144] a) 2-Chloro-6-m-tolyloxybenzonitrile

[0145] To a suspension of sodium hydride (60% in oil, 550 mg, 14 mmol)in DMSO (15 mL) was added a solution of m-cresol (1.5 g, 14 mmol) inDMSO (15 mL). The reaction was stirred at ambient temperature for 15minutes, at which time was added a solution of 2,6-dichlorobenzonitrile(2.3 g, 13 mmol) in DMSO (75 mL). The reaction was heated at 100° C. for20 hours, allowed to cool to ambient temperature, and poured into water(500 mL). The resultant mixture was extracted with ethyl acetate (2×200mL) and the combined extracts washed with 10% sodium hydroxide (300 mL)and water (300 mL), dried over magnesium sulfate, and concentrated togive 2-chloro-6-m-tolyloxybenzonitrile (2.4 g, 71%).

[0146] b) 4-(3-Chloro-2-cyano-phenoxy)-2-methyl-benzenesulfonyl chloride

[0147] To a cooled (0° C.) solution of 2-chloro-6-m-tolyloxybenzonitrile(1.1 g, 4.6 mmol) in dichloromethane (25 mL) was added dropwisechlorosufonic acid (0.46 mL, 7.0 mmol). The reaction was allowed toslowly warm to ambient temperature and maintained for 4 hours, at whichtime it was concentrated and diluted with ether (30 mL). The resultantsolution was then washed with ice cold water (25 mL) and brine (25 mL),dried over magnesium sulfate, and concentrated to furnish a pale yellowoil (690 mg, 43%) which solidified upon standing.

[0148] Examples 16a, 18a and 19a were prepared as set forth in Example17a substituting the appropriate starting materials. Example Compound

4-(3-Chloro-2-cyano-phenoxy)-2-chloro- benzenesulfonyl chloride 15a

4-(3-Chloro-2-cyano-phenoxy)-2,6-dimethyl- benzenesulfonyl chloride 17a

4-(3-Chloro-2-cyano-phenoxy)-2-methyl-5- methoxy-benzenesulfonylchloride 26a

EXAMPLE 27 4,5-Dimethoxy-biphenyl-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide

[0149]

[0150] a) 2-Bromo-4,5-dimethoxybenzenesulfonyl chloride

[0151] To a cooled (0° C.) solution of 4-bromoveratrole (15 mL, 100mmol) in dichloromethane (100 mL) was added dropwise chlorosufonic acid(26 mL, 400 mmol). The reaction was allowed to slowly warm to ambienttemperature and maintained for 3 hours, at which time it wasconcentrated and diluted with ether (300 mL). The resultant solution wasthen washed with ice cold water (2×250 mL) and brine (100 mL), driedover magnesium sulfate, and concentrated to furnish a grayish powder (25g, 78%).

[0152] b)2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide

[0153] To a solution of 3-[2-(N,N-dimethylamino)ethoxy]-4-chloroaniline(1.9 g, 8.8 mmol) in dichloroethane (50 mL) was added2-bromo-3,4-dimethoxybenzenesulfonyl chloride (2.8 g, 8.8 mmol). Theresultant solution was maintained at ambient temperature for 3 days,then concentrated. Crystallization from ethanol gave the title compound(3.4 g, 72%). MS (ES+) m/e 493 [M+H]⁺

[0154] c) 4,5-Dimethoxy-biphenyl-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide

[0155] To a solution of2-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide(50 mg, 0.1 mmol) in dimethoxyethane/water (25:3, 2 mL) was addedphenylboronic acid (120 mg, 1.0 mmol), cesium carbonate (820 mg, 2.5mmol), and tetrakispalladium triphenylphosphine (6 mg, 0.005 mmol). Theresultant mixture was heated at 90° C. for 16 hours, at which time itwas diluted with ethyl acetate (10 mL) and washed with 5% sodiumhydroxide (2×10 mL) and brine (10 mL). The solution was then dried overmagnesium sulfate and concentrated to give a yellow oil. Purification byHPLC (gradient; 10% acetonitrile/water to 90% acetonitrile/water)furnished the title compound (15 mg, 31%) as a white solid. MS (ES+) m/e491 [M+H]⁺

[0156] Example 20 was prepared as outlined in Example 19, substitutingthe appropriate starting materials. MS (ES+) m/e Example Compound [M+H]⁺

2-Benzo[1,3]dioxol-5-yl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5- dimethoxy-benzenesulfonamide 535 28

EXAMPLE 294-(Chloro-cyano-phenoxy)-N-[4-chloro-3-(3-diethylamino-propyl)-phenyl]-benzenesulfonamide

[0157]

[0158] a) (E)-3-(5-Amino-2-chloro-phenyl)-N,N-diethylacrylamide

[0159] To a solution of 2-chloro-5-nitrocinnamic acid (10 g, 40 mmol) inchloroform (130 mL) was added diethylamine (5.5 mL, 50 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10 g, 50mmol), and 1-hydroxybenzotriazole hydrate (7.1 g, 50 mmol). The reactionwas stirred at ambient temperature for 4 days, at which time it waswashed with saturated aqueous sodium bicarbonate (3×100 mL), 5% aqueoushydrogen chloride (3×100 mL), and brine (100 mL). The solution was thendried over magnesium sulfate and concentrated to give the title compound(12 g, 97%) as a white solid.

[0160] b) 3-(5-Amino-2-chloro-phenyl)-N,N-diethylpropionamide

[0161] To a solution of(E)-3-(5-amino-2-chloro-phenyl)-N,N-diethylacrylamide in ethyl acetate(50 mL) was added 5% platinum on carbon (1.5 g, 15 weight %). Theresultant mixture was chraged with hydrogen (50 psi) and agitated for 20hours, at which time it was filtered through Celite and concentrated togive the title compound (7.5 g, 83%) as a pale yellow oil. MS (ES+) m/e255 [M+H]⁺

[0162] c) 4-Chloro-3-(3-diethylaminopropyl)-phenylamine

[0163] To a solution of3-(5-amino-2-chloro-phenyl)-N,N-diethylpropionamide (3.6 g, 14 mmol) intetrahydrofuran (50 mL) was added a solution of borane-tetrahydrofurancomplex (1 M in tetrahydrofuran, 57 mL, 57 mmol). The resultant solutionwas heated at reflux for 24 hours, allowed to cool, and treated dropwise(over 15 minutes) with concentrated hydrochloric acid (4 mL) untilsolution became turbid. The mixture was stirred at ambient temperaturefor 1 hour, at which time it was concentrated. The residue was dilutedwith 10% aqueous sodium hydroxide (100 mL) and extracted with ethylacetate (2×100 mL). The extracts were washed with brine (100 mL), driedover sodium sulfate, and concentrated to give the title compound (3.0 g,88%) as a colorless oil. MS (ES+) m/e 241 [M+H]⁺

[0164] d)4-(Chloro-cyano-phenoxy)-N-[4-chloro-3-(3-diethylamino-propyl)-phenyl]-benzenesulfonamide

[0165] To a solution of 4-chloro-3-(3-diethylaminopropyl)-phenylamine(240 mg, 1.0 mmol) in chloroform (5 mL) was added4-(3-chloro-2-cyano-phenoxy)-benzenesulfonyl chloride (330 mg, 1.0mmol). The resultant solution was maintained at ambient temperature for24 hours, at which time it was concentrated to give an oily residue.Purification of the residue by HPLC (gradient; 10% acetonitrile/water to90% acetonitrile/water) furnished a yellow oil, which was subsequentlydissolved in methanol (1 mL) and treated with 1 M hydrogen chloride inether (1.5 mL) and stirred for 1 hour. Concentration of the mixture gavethe title compound (69 mg, 13%) as a pale yellow solid. MS (ES+) m/e 521[M+H]⁺

EXAMPLE 30N-[4Chloro-3-(2-dimethylamino-propoxy)-phenyl]-4-(3-chloro-2-methyl-phenoxy-benzenesulfonamide

[0166]

[0167] a) [4-Chloro-3-(2-oxo-propoxy)-phenyl]-carbamic acid tert-butylester

[0168] To a solution of (4-chloro-3-hydroxy-phenyl)-carbamic acidtert-butyl ester (240 mg, 1.0 mmol) and 1-chloropropan-2-one (220 mg,2.0 mmol) in acetone (30 mL) was added potassium carbonate (340 mg, 2.0mmol) and potassium iodide (16 mg, 0.1 mmol). The reaction mixture washeated at reflux for 16 hours, at which time it was concentrated. Theresultant residue was diluted with water (20 mL) and extracted withethyl acetate (2×20 mL). The combined organics were washed with brine(20 mL), dried over magnesium sulfate, and concentrated. Purification ofthe residue by flash chromatography (gradient; 10% ethyl acetate/hexanesto 20% ethyl acetate/hexanes) gave[4-chloro-3-(2-oxo-propoxy)-phenyl]-carbamic acid tert-butyl ester (210mg, 70%).

[0169] b) 4-Chloro-3-(2-dimethylamino-propoxy)-phenylamine

[0170] To a solution of [4-chloro-3-(2-oxo-propoxy)-phenyl]-carbamicacid tert-butyl ester (500 mg, 1.6 mmol) in methanol (30 mL) was addeddimethylamine hydrochloride (260 mg, 3.2 mmol) and 3 angstrom molecularsieves. The reaction mixture was heated at reflux for 16 hours, at whichtime it was allowed to cool and charged with sodium cyanoborohydride(200 mg, 3.2 mmol) and stirred at ambient temperature for 3 days.Methanol was removed via evaporation and the residue treated with 6 Nhydrogen chloride (30 mL). The resultant mixture was stirred at ambienttemperature for 4 hours, at which time it was diluted with water (50 mL)and washed with ether (50 mL). The aqueous layer was then basified withpotassium hydroxide (until pH>10) and extracted with ether (2×50 mL).The combined organics were washed with water (50 mL) and brine (50 mL),dried over magnesium sulfate, and concentrated to furnish4-chloro-3-(2-dimethylamino-propoxy)-phenylamine (120 mg, 50%). MS (ES+)m/e 229 [M+H]⁺

[0171] c)N-[4-Chloro3-(2-dimethylamino-propoxy)-phenyl]-4-(3-chloro-2-methyl-phenoxy)-benzenesulfonamide

[0172] To a solution of 4-chloro-3-(2-dimethylamino-propoxy)-phenylamine(100 mg, 0.5 mmol) in chloroform (10 mL) was added4-(3-chloro-2-cyano-phenoxy)-benzenesulfonyl chloride (160 mg, 0.5mmol). The resultant solution was maintained at ambient temperature for24 hours, at which time it was concentrated to give an oily residue.Purification of the residue by flash chromatography(94:5:1-dichloromethane/methanol/ammonium hydroxide) furnished the titlecompound (26 mg, 10%) as a sticky yellow solid. MS (ES+) m/e 509 [M+H]⁺

[0173] Examples 23 and 24 were prepared as set forth in Example 22,substituting the appropriate starting materials. MS (ES+) m/e ExampleCompound [M+H]⁺

4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-((S)-3-dimethylamino-but-2-oxy)-phenyl]- benzenesulfonamide 534 31

4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-((R)-3-dimethylamino-but-2-oxy)-phenyl]- benzenesulfonamide 534 32

EXAMPLE 334-(3-chloro-2-cyano-phenoxy)-N-[3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenyl]-benzenesulfonamide

[0174]

[0175] a) Benzhydrylidine-(3-fluoro-4-trifluoromethyl-phenyl)-amine.

[0176] A mixture of 4-amino-2-fluorobenzotrifluoride (5.0 g, 28 mmol)and benzophenone imine (4.7 mL, 5.1 g, 28 mmol) was heated at 150° C.for 3 h. After cooling to rt, the reaction mixture was vacuum filteredthrough a pad of silica gel eluting successively with hexanes, 4% and10% EtOAc in hexanes to afford the title compound as a yellow oil; yield3.5 g (36%): LCMS 344 (M⁺+H)

[0177] b) 3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenylamine

[0178] To a solution of 2-dimethylaminoethanol (0.65 g, 7.3 mmol) in DMF(73 mL) was added NaH (60% in mineral oil, 0.29 g, 7.3 mmol) at rt. Thereaction mixture was stirrred at rt for 1 h andbenzydrylidine-(3-fluoro-4-trifluoromethyl-phenyl)-amine (1.0 g, 2.9mmol) was added. After heating at 100° C. for 3 h, the reaction mixturewas cooled to rt and poured into sat'd. aq. NH₄Cl, extracted with EtOAcand the organic phase was concentrated under reduced pressure. Theresidue was treated with 1N HCl (100 mL) was heated at reflux for 0.5 h.The reaction mixture was cooled and extracted with ether. The aqueousphase was neutralized with 10% aq. NaOH and extracted with EtOAc. Theorganic phase was concentrated under reduced pressure to afford thetitle compound as a red oil; yield 0.25 g (35%): LCMS 249 (M⁺+H).

[0179] c)4-(3-chloro-2-cyano-phenoxy)-N-[3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenyl]-benzenesulfonamide

[0180] To a mixture of3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenylamine (0.10 g, 0.4mmol) in CHCl₃ (2.5 mL) was added 4-(3-chloro-2-cyano-phenoxy)benzenesulfonyl chloride (0.13 g, 0.4 mmol) at rt. After stirring at rtfor 72 h, the solvent was evaporated and the residue was purified byvacuum filtration through silica gel eluting successively with 4% MeOHin CH₂Cl₂ and 10% MeOH in CH₂Cl₂ followed by a mixture of CH₂Cl₂, MeOHand conc. NH₄OH (90:10:1). The solvent was removed from the desiredfractions and the residue was recrystallized from a mixture of MeOH andEtOAc to afford the title compound as a white solid; yield 0.01 g (5%):LCMS 540 (M⁺+H).

EXAMPLE 34

[0181] Formulations for pharmaceutical use incorporating compounds ofthe present invention can be prepared in various forms and with numerousexcipients. Examples of such formulations are given below.Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of Form.I) 2. Corn Starch 20 mg 3. Alginic acid 20 mg 4. Sodium Alginate 20 mg5. Mg stearate 1.3 mg  2.3 mg 

[0182] Procedure for Tablets:

[0183] Step 1: Blend ingredients No. 1, No. 2, No. 3 and No. 4 in asuitable mixer/blender.

[0184] Step 2: Add sufficient water portion-wise to the blend from Step1 with careful mixing after each addition. Such additions of water andmixing until the mass is of a consistency to permit its conversion towet granules.

[0185] Step 3: The wet mass is converted to granules by passing itthrough an oscillating granulator using a No. 8 mesh (2.38 mm) screen.

[0186] Step 4: The wet granules are then dried in an oven at 140° F.(60° C.) until dry.

[0187] Step 5: The dry granules are lubricated with ingredient No. 5.

[0188] Step 6: The lubricated granules are compressed on a suitabletablet press.

[0189] Inhalant Formulation

[0190] A compound of Formula I, (1 mg to 100 mg) is aerosolized from ametered dose inhaler to deliver the desired amount of drug per use.

[0191] Parenteral Formulation

[0192] A pharmaceutical composition for parenteral administration isprepared by dissolving an appropriate amount of a compound of formula Iin polyethylene glycol with heating. This solution is then diluted withwater for injections Ph Eur. (to 100 ml). The solution is thensterilized by filtration through a 0.22 micron membrane filter andsealed in sterile containers.

[0193] The above specification and Examples fully disclose how to makeand use the compounds of the present invention. However, the presentinvention is not limited to the particular embodiments describedhereinabove, but includes all modifications thereof within the scope ofthe following claims. The various references to journals, patents andother publications which are cited herein comprise the state of the artand are incorporated herein by reference as though fully set forth.

What is claimed is:
 1. A compound of Formula (I):

wherein: Ar is phenyl, thienyl, furanyl, pyridinyl, oxazoyl, pyrroyl,triazinyl, imidazoyl, pyrimidinyl, pyrazinyl, oxadiazoyl, pyrazoyl,triazoyl, thiazoyl, thiadiazoyl, quinolinyl, quinazolinyl,naphthyridinyl, azaspirononoyl, benzodioxanyl, benzodioxoyl, orbenzodioxepinyl, substituted or unsubstituted by one, two, three or fourof the following: halogen, CN, S(C₁₋₆ alkyl), CF₃, OCF₃, SCF₃, C₁₋₆alkyl, C₁₋₆ alkoxy, CO₂(C₁₋₆ alkyl), NR₉R₁₀, CONR₇R₈, or NO₂; A isphenyl, thienyl, furanyl, pyridinyl, oxazoyl, pyrroyl, triazinyl,imidazoyl, pyrimidinyl, pyrazinyl, N-phenylpyrroyl, oxadiazoyl,pyrazoyl, triazoyl, thiazoyl, thiadiazoyl, naphthyl, indoyl, quinolinyl,quinazolinyl, naphthyridinyl, benzothiophenyl, benzofuranyl,benzothiazoyl, benzoxazoyl, benzodioxanyl, benzodioxoyl,benzodioxepinyl, benzothiadiazoyl, benzoxadiazoyl, or benzimidazoyl, allof which may be substituted or unsubstituted by one, two, three or fourhalogens, C₁₋₆ alkyl, C₁₋₆ alkoxy, CO₂(C₁₋₆ alkyl), CN, or CF₃ groups; Yis O, NH, —S(O_(n))—, CH₂, or a bond; R₂ is hydrogen, halogen, CF₃, CN,or C₁₋₄ alkyl; R₃, R₄, R₇, and R₈ are independently hydrogen, C₁₋₆alkyl, or benzyl; R₅, R₆, R₉, and R₁₀ are independently hydrogen or C₁₋₆alkyl; X is O, S, or CH₂; n is 0, 1, or 2; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein Aris phenyl, benzodioxoyl, or pyrimidinyl which may be substituted orunsubstituted by halogen, CN, S(C₁₋₆ alkyl), CF₃, C₁₋₆ alkyl, C₁₋₆alkoxy, or NO₂; A is phenyl or thienyl which may be substituted orunsubstituted by halogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; Y is O, —S(O₂)—,or a bond; R₂ is halogen or CF₃; R₃ is C₁₋₆ alkyl; R₄ is C₁₋₆ alkyl; R₅and R₆ are hydrogen; R₇, R₈ R₉ and R₁₀ are hydrogen; and X is O or CH₂.3. A compound according to claim 1 wherein Ar is phenyl which may besubstituted or unsubstituted by halogen, CN, SMe, YCF₃, C₁₋₄ alkyl orNO₂; A is phenyl substituted or unsubstituted by halogen or methyl; R₂is halogen; R₃ is methyl or ethyl; R₄ is methyl or ethyl; R₅ and R₆ arehydrogen; R₇, R₈ R₉ and R₁₀ are hydrogen; X is O; and Y is an O or abond.
 4. A compound according to claim 1 chosen from the groupconsisting of:4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;5-Benzenesulfonyl-thiophene-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;3,5-Dichloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-chloro-4-nitro-phenoxy)-benzenesulfonamide;5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3-(4-chloro-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-phenoxy-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(4-methoxy-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,4-dichloro-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-chloro-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-methyl-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-trifluoromethyl-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,5-dichloro-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3,4-dichloro-phenoxy)-benzenesulfonamide;N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3-(3,5-dichloro-phenoxy)-benzenesulfonamide;2-Chloro-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;2-Methyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;2,6-Dimethyl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(4-chloro-phenoxy)-benzenesulfonamide;3,5-Dichloro-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-4-(2-chloro-4-nitro-phenoxy)-benzenesulfonamide;N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-phenoxy)-benzenesulfonamide;N-[4-Chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(3-chloro-phenoxy)-benzenesulfonamide;Biphenyl-4-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;4′-Chloro-biphenyl-4-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;3′,4′-Dichloro-biphenyl-4-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-benzenesulfonamidehydrochloride;2-methyl-5-methoxy-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4-(2-cyano-3-chloro-phenoxy)-benzenesulfonamide;4,5-Dimethoxy-biphenyl-2-sulfonic acid[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide;2-Benzo[1,3]dioxol-5-yl-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide;4-(Chloro-cyano-phenoxy)-N-[4-chloro-3-(3-diethylamino-propyl)-phenyl]-benzenesulfonamide;N-[4-Chloro-3-(2-dimethylamino-propoxy)-phenyl]-4-(3-chloro-2-methyl-phenoxy)-benzenesulfonamide;4-(3-Chloro-2-cyano-phenoxy)-N-[4-chloro-3-((S)-3-dimethylamino-but-2-oxy)-phenyl]-benzenesulfonamide;4-(3-Chloro-2-cyano-phenoxy)-N-[4chloro-3-((R)-3-dimethylamino-but-2-oxy)-phenyl]-benzenesulfonamide;and4-(3-chloro-2-cyano-phenoxy)-N-[3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenyl]-benzenesulfonamide.5. A compound according to claim 1 chosen from the group consisting of:4-(3-Chloro-2-cyano-phenoxy)N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;4-(2-chloro-4-nitro-phenoxy)N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-3,5-dichloro-benzenesulfonamide;3-(3,5-Dichloro-phenoxy)N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-benzenesulfonamide;4-(2-cyano-3-chloro-phenoxy)N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-chloro-benzenesulfonamide;4-(2-cyano-3-chloro-phenoxy)N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2-methyl-benzenesulfonamide;4-(2-cyano-3-chloro-phenoxy)N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2,6-dimethyl-benzenesulfonamide;and4-(3-chloro-2-cyano-phenoxy)-N-[3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenyl]-benzenesulfonamide.6. A pharmaceutical composition comprising a compound of formula (I) ofclaim 1 and a pharmaceutically acceptable carrier or excipient.
 7. Amethod of treating conditions associated with Urotensin-II imbalance byantagonizing the Urotensin-II receptor which comprises administering toa patient in need thereof, a compound of Formula I of claim
 1. 8. Amethod according to claim 7 wherein the disease is congestive heartfailure, stroke, ischemic heart disease, angina, myocardial ischemia,cardiac arrhythmia, essential and pulmonary hypertension, renal disease,acute and chronic renal failure, end stage renal disease, peripheralvascular disease, male erectile dysfunction, diabetic retinopathy,intermittent claudication/ischemic limb disease, ischemic/hemorrhagicstroke, COPD, restenosis, asthma, neurogenic inflammation, migraine,metabolic vasculopathies, bone/cartilage/joint diseases, arthritis andother inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis,atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitivedisorders, Alzheimers disease, impulsivity, anxiety, stress, depression,parkinsons, movement disorders, sleep-wake cycle, incentive motivation,pain, neuromuscular function, diabetes, gastric reflux, gastric motilitydisorders, ulcers and genitourinary diseases.